It is a common observation that when poorly soluble, hydrophobic drug substances are employed in the preparation of solid dosage forms such as tablets or capsules, their rate of dissolution is rather slow. As a result, their absorption from the gastrointestinal tract into systemic blood of the body is also slow. However, if such drugs are to be administered in oral dosage forms and to be used for clinical indications where a rapid onset of therapeutic activity is desirable, the slow rate of dissolution and slow rate of absorption can put very great limitations on their therapeutic utility.
A frequently used method to overcome such problems is to finely grind or `micronise` drug substances so as to reduce their particle-size. For example high speed running pin mills or air-jet mills are used to reduce the particle-size to a range of 5-10 microns. A major disadvantage of such grinding methods is the resulting tendency of the milled particles to agglomerate and the formation of an electrostatic charge on their surfaces which leads to poor flow and wetting of the particles. These disadvantages may even negative the very purpose of obtaining a faster rate of dissolution by the particle-size reduction. (Aguiar et al. Journal Pharm. Sci. 1967, 56, page 1243- and Monkhouse et al. Journal Pharm. Sci. 1972, 61, page 1430 et. seq.).
One highly useful class of drugs is the benzodiazepines. These are mostly used as sedatives and tranquilisers. Almost all members of this class of drugs, with few exceptions, are practically insoluble or very slightly soluble in water. Their formulation into oral solid dosage-forms presents a general problem. It is also known that among the various benzodiazepines large differences exist with regard to their metabolism and pharmacokinetic properties. (Breimer et al. Drug Research 1980, 30 (1) no. 5a, page 875-). Some benzodiazepine drugs such as diazepam and flurazepam are eliminated from the body at a relatively slow rate with formation of active metabolites. Others such as temazepam and oxazepam are metabolised rather rapidly and without the formation of active metabolites. These differences are clinically important since pharmacokinetic factors determine the duration of action of a drug and also the dosage required. In making use of a drug in different clinical indications, the required duration of their action may be very different. In case of antianxiety or anticonvulsant therapy there is a need for continuous treatment which may extend over a long period of time. There is hence a need for parent drugs or those having active metabolites with a long elimination half-life. On the other hand if a drug is to be used as a hypnotic it is desirable that a drug with a shorter half-life and whose duration of action can be restricted to the night be used preferably. This can ensure that no hangover effects of sedation are felt on awakening the following day.
Ideally drugs and pharmaceutical compositions containing them, to be used as hypnotics should have the following properties:
(a) a rapid onset of activity following their administration
(b) the activity should last for a period corresponding to that of normal sleep duration of 8-10 hours.
(c) there should be a minimum residual sedation after a period of 10 to 12 hours so that the subject can attend to his/her normal daily routine after awakening.
Although most of the benzodiazepine drugs are used as tranquilisers and sedatives, a few members of this class have been used as hypnotics. Nitrazepam and flurazepam are the typical examples of compounds that have been employed as hypnotics. However, due to their long half-life and the formation of active metabolites they are reported to cause the typical `side effects` of sedation and morning hangover. Another benzodiazepine compound with an intermediate half-life that has recently been increasingly used as hypnotic is temazepam (7 chloro-1,3 dihydro-3-hydroxy-1, methyl-5 phenyl-2H-1,4 benzodiazepine-2-one). Due to its pharmacokinetic profile and little formation of active metabolites it has been found to be a very suitable hypnotic; however, due to its poor solubility the marketed hard gelatine dosage-form has been said to be not satisfactory. A publication (Fucella et al. Europ. Jour. Clin. Pharmacol. 1977, 12, pages 383-386) reported that a soft gelatine capsule formulation containing the drug in dissolved form showed a relatively faster absorption and a shorter time to reach peak blood concentration as compared to a hard-gelatine capsule formulation containing the drug in powder form. There has also been reported an inconsistent efficacy of this drug compound when contained in a hard gelatine capsule formulation (Miller, Pharmacotherapy, 1981, 1, pages 3-13).
Another similar benzodiazepine drug with an intermediate half-life (ca. 8-12 hours) is oxazepam (7-chloro-1,3 dihydro-3-hydroxy-5-phenyl-2H-1,4 benzodiazepine-2-one). It is available in the U.S.A. under the name Serax (Wyeth Laboratories) in dosage strengths of 10, 15 and 30 mg in the form of hard gelatine capsules and also as a 15 mg tablet. In several European countries however it is sold under the name Seresta as a 15 mg tablet and Seresta Fort as a 50 mg tablet. The therapeutic use of oxazepam as a tranquiliser is very well established but its use as a hypnotic has been a matter of controversy. In the year 1980 the British Committee on Review of Medicines published guidelines for the therapeutic use of various benzodiazepine drugs (British Medical Journal, Mar. 28, 1980, page 912). It was specifically mentioned therein that oxazepam is not to be recommended for hypnotic use but only as a tranquiliser. In some other countries like France, however, oxazepam in the form of Seresta Fort (50 mg) tablets is occasionally used as a hypnotic with the result that side effects of sedation and next morning sedation are frequently observed. Since oxazepam is practically insoluble in water and has a slow rate of dissolution and absorption, it also results in a longer time for the onset of sleep. It could perhaps be used as a good hypnotic provided it were possible to increase its rate of dissolution by either a formulation or some other method. This may eventually also enable the use of an optimal lower dose of oxazepam as a hypnotic than Seresta Fort as 50 mg tablets and thus reduce the incidence of side effects observed with the present dosage form.
It is hence an object of this invention to develop an improved solid dosage-form (capsule or tablet) containing oxazepam in a dose lower than 50 mg which shows rapid dissolution and absorption and thus a shorter time for sleep induction by rapidly achieving the equivalent maximum blood concentration to that reached more slowly by Seresta Fort, so that oxazepam can be used as a hypnotic. A further aim of this invention is to develop a process which is applicable in general to almost all or most of the "practically water insoluble drugs" so that they can be easily formulated into solid dosage-forms showing a fast rate of dissolution and absorption.
As has been mentioned above a conventional method for increasing the rate of dissolution of solids is by reduction of their particle size by micronisation or similar dry grinding methods. This, however, often leads to agglomerate formation of the milled product due to its poor wetting properties and is not helpful in increasing dissolution. Other approaches adopted to overcome these problems involve formation of "solid dispersions or solid-solid solutions". This involves the melting together of the drug and excipients such as sugars, urea, or polyvinylpyrrolidone etc. (J. L. Ford, Pharm. Acta Helvetica, 1986, 61, (3), 69-88 "The current status of solid dispersions"). Another approach has been to form "inclusion compounds" of some drugs by their complexation with cyclodextrines (Uekama K. et al. Internat. Jour. Pharmaceutics, 1983, 16, pages 327-388). Both the above mentioned processes are applicable to a few drugs and also only to a very limited extent. The comprehensive literature review by J. L. Ford refers to more than 120 drugs that have been used in the evaluation of solid-dispersion techniques.
Another technique that has been extensively used in the field of analytical chemistry of "adsorption chromatography" makes use of adsorption of drugs on some inorganic carriers such as silicates and some special types of aluminates etc. Some workers have also applied this method to investigate the adsorption of certain drugs on such inorganic supports having a large "internal porous surface area" so that their dissolution rate and solubility could be increased by desorption in the dissolving medium. The adsorption properties of drugs on such carriers however, depend mainly on the functional groups present as also the internal surface area and the pore volume of the support materials employed (Rupprecht H., Progr. Coll. and Polymer Sci., 1976, 60, 194-202). A few studies employing Montmorillonit (Veegum) as carrier have been also reported in the literature (SU and Cartensen, Jour. Pharm. Sci., 1972, 61, pp. 420-424 and Monkhouse et al., Jour. Pharm. Sci., 1972, 61, pg. 1430-1435).
The problem to be solved by the present invention is to provide an orally administrable pharmaceutical composition including a hydrophobic drug and a carrier in which the drug is quickly dissolved and adsorbed.